The hypothesis underlying this project is that HIV-1 envelope immunogenicity phenotypes, or immunotypes, can be defined that will be associated with the capacity to induce broadly cross-reactive, primary virus neutralizing antibody responses. The project is designed to test this hypothesis with respect to properties of envelope proteins from strains of HIV-1 representative of those currently prevalent in China. The rationale for the focus on these strains is that the complex, rapidly emerging epidemic in China is an appropriate focus for research regarding potential HIV vaccine efficacy trials. The highly potent in vivo expression system that will be used in these studies is the Venezuelan equine encephalitis virus (VEE) replicon system. In Aim 1 we will evaluate the infectivity and neutralization sensitivity phenotypes of HIV-1 envelopes with broadly cross-reactive neutralization sensitivity and immunogenicity. The relationships between the in vitro phenotypes of these envelopes and the immunotypes of envelopes with other specific neutralizing and infectivity phenotypes will be evaluated. These studies will lead to the selection and design of clade B immunogen for user in primate immunogenicity and challenge studies. In Aim 2 we will develop clade C and E envelopes with broad neutralizing cross-reactivity, based on in vitro reactivity and immunogenicity. Envelope phenotypes associated with desired immunotype in Aim 1 will be sought or designed to facilitate achievement of this goal. In Aim 3 of this project we will study the induction of cross-reactive neutralizing in rhesus macaques and the protective efficacy of these responses against homologous and heterologous SHIV challenge. The envelopes with the appropriate immunotypes, as defined and developed in this project, will be provided to Project 2 for development of soluble, oligomeric protein immunogens. The potential for improvement of responses associated with HIV-1env- VEE replicon or soluble GUV01 oligomer immunization by combination of the two modalities in a prime-boost regimen will be evaluated. The optimum envelope immunization regimen will be combined with the optimum CTL induction regimen developed in Project 3. The comparative efficacies of the immunization methods and of the optimized neutralization plus CTL induction regimens will be determined in SHIV challenge models. This project is central to the overall goals of the multiproject program. The combination of the immunogens developed in Projects 2 and 3 with the immunogens developed in this project will be evaluated in small animals and in monkeys. Envelope genes produced in this project will be used for production of oligomeric envelope in Project 2. Sera from Chinese donors obtained in this project will be used in Project 2. This project will interact with each of the cores. Overall, we will determine the extent to which broadly cross-reactive neutralizing antibodies and cytotoxic T cells can protect non-human primates against experimental challenge with SHIV.